In‐vitro and in‐vivo evaluation of chitosan‐based thermosensitive gel containing lorazepam NLCs for the treatment of status epilepticus

Abstract

The objective of this study was to develop an in-situ gel containing lorazepam (LZM) loaded nanostructured lipid carriers (NLCs) for direct nose-to-brain delivery in order to increase drug therapeutic efficacy in the treatment of epilepsy. Accordingly, LZM loaded NLCs were formulated using emulsification solvent diffusion and evaporation method; then the effects of the formulation variables on different physicochemical characteristics of NLCs were investigated. Thermosensitive in-situ gels containing LZM-NLCs were prepared using a combination of chitosan and β-glycerol phosphate (β-GP). The anticonvulsant efficacy of LZM-NLCs-Gel was then examined using the pentylenetetrazole (PTZ) model. The optimised NLCs were spherical, showing the particle size of 71.70 ± 5.16 nm and the zeta potential of −20.06 ± 2.70 mV. The pH and gelation time for the chitosan solution with 15% (w/v) β-GP were determined to be 7.12 ± 0.03 and 5.33 ± 0.58 min, respectively. The in-vivo findings showed that compared with the control group and the group that received LZM-Gel, the occurrence of PTZ-induced seizures in the rats was significantly reduced by LZM-NLCs-Gel after intranasal administration. These results, therefore, suggested that the LZM-NLCs-Gel system could have potential applications for brain targeting through nasal route and might increase LZM therapeutic efficacy in the treatment of epilepsy.

On a highway to the brain: A review on nose-to-brain drug delivery using nanoparticles

“…The IN administration of this formulation achieved a significant reduction of pentylenetetrazole-induced seizures in rats or diminished the seizure intensity compared with a control group and those treated with an in-situ gel containing the free drug, both by IN route; suggesting that the incorporation of NLC into in situ gels could improve the therapeutic drug effect. Moreover, the authors related these outcomes with the small size of NLC, which might allow their transcellular passage by olfactory neurons towards the brain via endocytic pathways of neuronal cells [85].…”

Pharmacokinetics and Pharmacodynamics of Intranasal Solid Lipid Nanoparticles and Nanostructured Lipid Carriers for Nose-to-Brain Delivery

“…For example, Plasmodium berghei ANKA-injected mice are used to evaluate the anti-cerebral malarial effects of artesunate [ 57 ], artemether, and lumefantrine [ 64 ]. In epilepsy, the maximal electroshock seizure model [ 79 , 80 , 81 ] or pentylenetetrazole-induced epilepsy rat model [ 82 , 83 , 84 ] are used. Treatment effects on Alzheimer’s disease and dementia are assessed using animals with scopolamine-induced amnesia [ 85 , 86 , 87 , 88 , 89 ] or streptozocin-induced Alzheimer’s disease [ 90 ].…”

“…In mice infected with fungal cells, NLCs (IN) reduced the fungal burden in the brain more than free ketononazole (IN). Taymouri et al developed NLCs containing lorazepam, a drug used to treat epilepsy [ 84 ]. The optimized NLC formulation was loaded into an in situ gel of CS and β-glycerol phosphate for nose-to-brain delivery.…”

“…Besides the longer nasal residence of gel (21.7 min versus 8 min), the use of thermoresponsive in situ gel with rapid gelation may have reduced the spread of formulation from the olfactory region to respiratory epithelium, and therefore increased drug transport via direct routes [ 27 ]. In another study, the occurrence of seizures in pentylenetetrazole-treated rats was lower for lorazepam-loaded NLC gel (IN) than a lorazepam-loaded NLC suspension (IN) [ 84 ].…”

Multiple Roles of Chitosan in Mucosal Drug Delivery: An Updated Review

“…The combined use of the in situ gel and suitable nanocarriers can allow the further improvement of the formulation effectiveness. For example, an in situ gel based on a mixture of CS and β-glycerol phosphate, containing nanostructured lipid carriers (NLCs) loaded with lorazepam was developed for direct nose-to-brain delivery of the drug; in vivo studies showed that the new “drug-in NLC-in gel formulation” was more effective than the corresponding “drug-in gel formulation” in reducing the pentylenetetrazol-induced seizures, proving its potential usefulness for brain targeting through the nasal route [ 160 ].…”